Insulin-like Growth Factor II mRNA-binding Protein 3 is a Highly Sensitive Marker for Intravascular Large B-cell Lymphoma: Immunohistochemical Analysis of 152 Pathology Specimens From 88 Patients.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive extranodal large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of blood vessels, particularly capillaries. IVLBCL lacks mass formation, and its diagnosis can be challenging. We analyzed the utility of insulin-like growth factor II mRNA-binding protein 3 (IMP3) immunohistochemistry for IVLBCL diagnosis in various organs. Double staining with paired box 5 (PAX5) was performed for validation. Overall, 152 pathological specimens (111 positive and 41 negative for IVLBCL) obtained from 88 patients with a diagnosis of IVLBCL were stained for IMP3 and IMP3/PAX5. As negative controls, 40 pathology specimens from 38 patients with no history of IVLBCL or other B-cell lymphomas were stained for IMP3, which comprised 31 benign pathological specimens from 29 patients in whom malignancy was suspected, 7 cases of appendicitis with intravascular and/or intralymphatic lymphoid proliferations, and 2 cases of intravascular natural killer/T-cell lymphoma. All mononuclear cells with cytoplasmic staining were considered positive for IMP3 expression, but expression restricted to germinal center B cells was excluded from evaluation. All 111 IVLBCL pathological specimens were positive for IMP3 and IMP3/PAX5. In addition, 11 of the 41 specimens originally diagnosed as IVLBCL-negative showed IMP3/PAX5 double-positive cells, raising the suspicion of IVLBCL. However, of the 40 negative control samples, IMP3-positive non-germinal center B cells were detected in only 2 samples ( P = 0.0131) and no intravascular IMP3-positive B cells suspicious for IVLBCL were identified. Altogether, IMP3 immunohistochemistry is a highly sensitive marker of IVLBCL and can be a helpful adjunct for IVLBCL diagnosis.

Metastatic prostate cancer with low PSA levels diagnosed after holmium laser enucleation of the prostate.

Holmium laser enucleation of the prostate is a widely accepted surgical treatment method for benign prostate hyperplasia, but its effect on prostate cancer remains unclear. In this study, we report the cases of two patients with metastatic prostate cancer diagnosed during follow-up after holmium laser enucleation of the prostate. Case 1 was a 74 year-old man who underwent holmium laser enucleation of the prostate. Prostate-specific antigen levels declined from 4.3 to 1.5 ng/mL at 1 month after surgery, but after 19 months, they increased to 6.6 ng/mL. Based on pathological and radiological findings, he was diagnosed as having prostate cancer, with Gleason score 5 + 4 with neuroendocrine differentiation, cT3bN1M1a. Case 2 was a 70 year-old man who also underwent holmium laser enucleation of the prostate. Prostate-specific antigen levels declined from 7.2 to 2.9 ng/mL at 6 months after surgery, but after 12 months, they increased to 12 ng/mL. Based on pathological and radiological findings, he was diagnosed as having prostate cancer, with Gleason score 4 + 5 with intraductal carcinoma of the prostate, cT3bN1M1a. This report suggests that advanced prostate cancer may be newly diagnosed after holmium laser enucleation of the prostate. Even if prostate cancer had not been demonstrated in the enucleated specimen, and postoperative PSA levels were below the standard values, physicians should regularly monitor prostate-specific antigen levels after holmium laser enucleation of the prostate, and further examination should be considered keeping in mind prostate cancer progression.

[A case of autopsy-confirmed duodenal perforation due to calcium polystyrene sulfonate].

A 77-year-old male patient was referred to our hospital because of jaundice. He was diagnosed with alcoholic liver cirrhosis and was admitted to our hospital because of liver failure. After admission, we observed conservative liver disease, but the liver damage did not improve and gradually worsened. Renal function deteriorated during liver failure. Hyperkalemia presented due to renal dysfunction. Hence, calcium polystyrene sulfonate (CPS) was initiated. He died because of liver failure although hyperkalemia improved. An autopsy revealed ulcer perforation with CPS crystals in the duodenum. A basic substance considered a crystal of CPS was found by hematoxylin and eosin staining from the ulcer adjacent to the perforation and the exudate attached to the peritoneum. Furthermore, a large amount of CPS crystals were found in the ascites. A final diagnosis of gastrointestinal perforation peritonitis due to CPS was made. Gastrointestinal perforation due to CPS is presumed as a direct mucosal injury due to the drug, most of which is the sigmoid colon of elderly patients. Upper gastrointestinal tract perforation is extremely rare. We experienced a case of autopsy in which duodenal perforation due to CPS was pathologically confirmed. CPS is a widely used drug for renal disorders, but it has a risk of gastrointestinal injury. Therefore, a potential gastrointestinal mucosal injury should be considered when using CPS.

Magnifying Narrow-Band Imaging with Acetic Acid Spray for Superficial Non-Ampullary Duodenal Epithelial Tumors Based on the Mucin Phenotype.

INTRODUCTION: This study aimed to identify the characteristics of superficial non-ampullary duodenal epithelial tumors (SNADETs) based on the mucin phenotype using magnifying narrow-band imaging with acetic acid spray (MA-NBI) and evaluate the efficacy of MA-NBI in differentiating gastric-type (G-type) from intestinal-type (I-type) lesions. METHODS: We retrospectively identified 59 resected SNADETs in 59 patients who underwent MA-NBI. We evaluated surface patterns using MA-NBI to differentiate G-type from I-type lesions. Surface structures were classified into three patterns: tubular, villous, or oval structures. Lesions displaying a single pattern among the three patterns were classified as monotype, whereas those displaying multiple surface patterns were classified as mixed type. In addition, lesions with disorganized and unclear structures with irregular margins were classified as irregular surface structures. RESULTS: In total, 32 (54%), 26 (44%), and 1 (2%) lesions were classified as Vienna category 3, 4, and 5 tumors, respectively, whereas 49 (83%) and 10 (17%) were classified as I- and G-type lesions, respectively. Oval structures were more frequently observed in G-type lesions (70%), whereas tubular structures were more frequently observed in I-type lesions (78%) (p < 0.001). Category 4 and 5 lesions had significantly higher mixed and irregular surface structure rates than category 3 lesions (41 vs. 6%, p = 0.003 and 81 vs. 3%, p < 0.001, respectively). CONCLUSION: MA-NBI can distinguish the mucin phenotypes of SNADETs and may facilitate histological grade diagnosis.

Skull metastases from extramammary Paget's disease emerging 8 years after initial treatment with no local progression: illustrative case.

BACKGROUND: The foci of distant metastasis from extramammary Paget's disease (EMPD) are the lung, liver, truncal bones, vertebrae, and brain. However, skull metastases have not been reported. OBSERVATIONS: The authors treated a patient with calvarial and skull base metastases from EMPD who had undergone wide local resection of EMPD 8 years before, and they report his clinical course. LESSONS: Because EMPD with distant metastasis is fatal, it should be recognized that EMPD can metastasize to the skull even when it seemed to be in remission for several years.

Late recurrence of early gastric cancer 11 years after curative endoscopic submucosal dissection.

A 73-year-old man was initially diagnosed with a 50-mm, depressed-type early gastric cancer on the anterior wall of the angulus, and the lesion was curatively resected en bloc by endoscopic submucosal dissection. Pathology revealed a 54 mm × 43 mm differentiated-type predominant adenocarcinoma with focal undifferentiated-type component that was confined to the mucosa without ulceration. Eleven years after endoscopic submucosal dissection, lymph node metastasis along the lesser curve was incidentally detected on magnetic resonance imaging and diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy. The patient received distal gastrectomy with D2 lymph node dissection. A resected lymph node revealed a well-differentiated adenocarcinoma with a poorly differentiated component; thus, the final diagnosis was late recurrence of early gastric cancer originally treated by endoscopic submucosal dissection. This report demonstrates that metastatic recurrence may occur in curative endoscopic submucosal dissection for early gastric cancer and that gastric cancer can recur even after more than 5 years.

Gastric Cancer with Multiple Lymph Node Enlargement at the Time of the Sarcoidosis Diagnosis.

An 80-year-old woman was found to have a 40-mm depressed-type gastric cancer. Computed tomography showed multiple lymph node enlargement, including paraaortic lymph nodes. The extent of lymph node enlargement was significant compared with the depth of the primary lesion. We conducted distal gastrectomy, D2 lymph node dissection, and a paraaortic lymph node biopsy. Microscopically, the tumor was diagnosed as mucosal cancer. In the dissected lymph nodes, noncaseating granuloma was found without metastasis of adenocarcinoma. Immunohistochemical staining using Propionibacterium acnes-specific antibodies showed a large number of P. acnes-positive cells in the granulomas. Finally, the tumor was diagnosed as early-stage gastric cancer and sarcoidosis.

Efficacy of Magnifying Narrow Band Imaging with Acetic Acid Spray in Diagnosing Superficial Non-Ampullary Duodenal Epithelial Tumors.

BACKGROUND/AIMS: The aim of the present study was to evaluate the efficacy of magnifying narrow band imaging with acetic acid spray (MA-NBI) in differentiating category 4/5 lesions from category 3 lesions of superficial non-ampullary duodenal epithelial tumors (SNADETs) as per Vienna Classification and to compare the diagnostic performances of both MA-NBI and magnifying narrow band imaging (M-NBI). METHODS: We retrospectively identified 60 resected SNADETs (31 category 3 lesions and 29 category 4/5 lesions) in 60 patients who underwent M-NBI and MA-NBI preoperatively. We evaluated vascular and surface patterns using M-NBI and MA-NBI for characterizing category 3 and 4/5 lesions. The surface pattern was classified as tubular, villous, or mix structure using MA-NBI. In addition, lesions with disorganized and unclear structures with irregular margins that can be clearly recognized by MA-NBI were defined as irregular surface structures. RESULTS: For MA-NBI, category 4/5 lesions had a significantly higher mix structure rate and higher irregular surface structure rate than category 3 lesions (62 vs. 16%, p < 0.001, and 86 vs. 19%, p < 0.001, respectively). The diagnostic accuracy of MA-NBI using mix and irregular surface structures for identifying category 4/5 lesions was as follows: sensitivity, 62/86%; specificity, 84/77%; positive predictive value, 78/78%; negative predictive value, 70/86%; and accuracy, 73/82%. The diagnostic accuracy of MA-NBI using irregular surface structure was significantly higher than that of M-NBI (p < 0.05). CONCLUSION: MA-NBI may be useful in differentiating between category 3 and category 4/5 lesions of SNADETs.

Upper Gastrointestinal Langerhans Cell Histiocytosis: A Report of 2 Adult Cases and a Literature Review.

Langerhans cell histiocytosis (LCH) with primary involvement of the upper gastrointestinal (GI) tract is rare. We report 2 adult cases of localized LCH in the upper-GI tract, including the second reported adult case of esophageal LCH and review 11 previously reported cases. Case 1 involved the esophagus of a 61-year-old man; histiocytosis was detected when endoscopy was performed for an examination of epigastric pain. Case 2 involved the stomach of a 56-year-old woman wherein the lesion was detected during a follow-up endoscopy after Helicobacter pylori infection. Both biopsy specimens exhibited diffuse proliferation of mononuclear cells with nuclear convolution and a background of eosinophilic infiltrate. The cells were immunohistochemically positive for CD1a and langerin, and BRAF V600E mutation was detected in Case 2. Follow-up endoscopy for both cases revealed that the lesions disappeared without any treatment. It is important to avoid misdiagnosing LCH of the upper-GI tract as a malignant neoplasm.

[A case of concomitant pancreatic neuroendocrine neoplasm and intraductal papillary mucinous neoplasm in which preoperative diagnosis was difficult].

A 75-year-old male patient has been followed-up for mixed-type intraductal papillary mucinous neoplasm (IPMN) in the tail of the pancreas for about 20 years. Upon close examination, he was diagnosed of high-risk stigmata due to a nodule having a contrast effect of 5mm or more in the tumor. Based on this, a distal pancreatectomy was performed. Histopathological analysis revealed concomitant IPMN (low-grade) and pancreatic neuroendocrine neoplasm (PNEN) (G1). This prompted us to report a very rare case of coexisting PNEN and IPMN with an interesting pathological finding that might suggest its pathogenic mechanism.

Fumarate hydratase-deficient renal cell carcinoma: A clinicopathological study of seven cases including hereditary and sporadic forms.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) has been incorporated into the recent international histological classification of renal tumors. However, to date, there are limited studies describing the clinicopathological features of fumarate hydratase (FH)-deficient RCC, including the hereditary (HLRCC) and sporadic forms. Herein, we present a clinicopathological study of seven cases with FH-deficient RCC. The age of patients ranged from 26 to 70 years with mean and median age of 51.7 and 57 years, respectively. The follow-up data of all patients were available. One patient was alive without the disease and five patients were alive with active disease. One patient died of the disease. Family history of RCC, or skin or uterine smooth muscle tumor within second degree of kinship was present in four of seven patients. Metastasis was observed in all tumors. Metastatic sites included bone, lungs, liver, peritoneum, ovaries, tonsils, or lymph nodes. Grossly, the cut surface of the tumor usually showed light brown, brown, or whitish color. Microscopically, the cytoplasm of the tumor cells was predominantly eosinophilic and all tumors displayed various architectural patterns such as papillary, tubular, solid, or microcystic patterns. Furthermore, two tumors demonstrated a tubulocystic pattern. Sarcomatoid change and rhabdoid features were seen in five tumors and two tumors, respectively. Large cytomegaloviral (CMV) inclusion-like eosinophilic nucleoli surrounded by a clear halo were identified in all tumors. All tumors showed negative immunohistochemical reaction for FH protein. False positive results of TFE3 protein were observed in three tumors. Furthermore, a germline mutation of FH gene was identified in one patient with family history of the disease. In conclusion, FH-deficient RCC includes hereditary and sporadic forms. Grossly, this tumor is solitary and occurs unilaterally. Histologically, the tumor is characterized by various patterns such as papillary, tubular, solid, tubulocystic, or microcystic, has eosinophilic cytoplasm and CMV-like high-grade nuclei. FH-deficient RCCs frequently metastasize to other anatomic sites. TFE immunoreactivity may occur in some FH-deficient RCCs, and immunohistochemistry can accurately diagnose these tumors and mutational analysis of FH gene.

Gastric MiNEN Arising from the Heterotopic Gastric Glands.

An 80-year-old woman presented with a 30-mm protruding lesion-like submucosal tumor with a central depression located at the anterior wall of the upper gastric body. The depressed area had a well-demarcated margin, while the other area was covered by a non-neoplastic mucosa. A biopsy specimen revealed neuroendocrine carcinoma. Endoscopic ultrasonography revealed a heterogeneous mass with a clearly distinguished border in the submucosal layer. The mass had two distinct areas adjacent to each other. In addition, a hypoechoic zone was observed on the margin of the mass. Distal gastrectomy was performed. The final diagnosis was a mixed neuroendocrine-non-neuroendocrine neoplasm arising from the heterotopic gastric gland.

Consecutive Prostate Cancer Specimens Revealed Increased Aldo⁻Keto Reductase Family 1 Member C3 Expression with Progression to Castration-Resistant Prostate Cancer.

Aldo-keto reductase family 1 member C3 (AKR1C3) is an enzyme in the steroidogenesis pathway, especially in formation of testosterone and dihydrotestosterone, and is believed to have a key role in promoting prostate cancer (PCa) progression, particularly in castration-resistant prostate cancer (CRPC). This study aims to compare the expression level of AKR1C3 between benign prostatic epithelium and cancer cells, and among hormone-naïve prostate cancer (HNPC) and CRPC from the same patients, to understand the role of AKR1C3 in PCa progression. Correlation of AKR1C3 immunohistochemical expression between benign and cancerous epithelia in 134 patient specimens was analyzed. Additionally, correlation between AKR1C3 expression and prostate-specific antigen (PSA) progression-free survival (PFS) after radical prostatectomy was analyzed. Furthermore, we evaluated the consecutive prostate samples derived from 11 patients both in the hormone-naïve and castration-resistant states. AKR1C3 immunostaining of cancer epithelium was significantly stronger than that of the benign epithelia in patients with localized HNPC (p < 0.0001). High AKR1C3 expression was an independent factor of poor PSA PFS (p = 0.032). Moreover, AKR1C3 immunostaining was significantly stronger in CRPC tissues than in HNPC tissues in the same patients (p = 0.0234). Our findings demonstrate that AKR1C3 is crucial in PCa progression.

[Granulomatous Prostatitis : Three Cases Report].

Case 1 : A 65-year-old man visited withfrequent urination and dysuria. Pyuria and bacteriuria were observed and prostate specific antigen (PSA) was elevated to 5.69 ng/ml. Prostate cancer and urinary tract infection were suspected. A antibiotics were administered and prostate magnetic resonance imaging (MRI) was performed. Massive prostate cancer was strongly suspected from the MRI findings and prostate needle biopsy was performed. The pathological examination revealed nonspecific granulomatous prostatitis. Case 2 : A 69-year-old man visited withfrequent urination. Urinalysis was normal and PSA was elevated to 4.52 ng/ml. Diffuse prostate cancer was suspected from the MRI findings and prostate needle biopsy was performed. Pathological findings were similar to those in case 1. Case 3 : A 61-year-old man presented withno urinary symptoms. Urinalysis was normal and PSA was elevated to 11.64 ng/ml. Medical history was renal pelvic cancer and bladder cancer. He had undergone a transurethral resection of the bladder tumor (TURBT) and intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Prostate cancer was suspected from the MRI findings and prostate needle biopsy was performed. Pathological findings were granulomatous prostatitis. In these three cases, the structure of these prostate capsules was preserved although extensive prostate cancer was suspected from the findings of MRI T2-weighted and diffusion weighted images. Although histopathologic examination is mandatory for differential diagnosis between granulomatous prostatitis and diffuse prostate cancer, prostate MRI may help to distinguish these diseases.

Early-stage Neuroendocrine Carcinoma of the Esophagus Observed with Annual Endoscopy for Three Years.

An 80-year-old man was found to have a reddish depressed lesion on the middle thoracic esophagus. The morphology of the lesion had been almost unchanged for 3 years, but it transformed to a 2-cm depressed lesion with elevated margins and an irregular nodular surface. The lesion was resected endoscopically and ultimately diagnosed as a combined neuroendocrine carcinoma and squamous cell carcinoma with submucosal invasion. The patient was additionally treated with chemoradiotherapy but died of the primary disease eight months after the initial treatment. It is important to elucidate the natural history of this disease at an early stage.

Progressive peripheral CD8+ T lymphocytosis complicated by pure red cell aplasia following immunosuppressive therapy for thymoma-associated myasthenia gravis.

We herein report a unique case of type B2 thymoma-associated myasthenia gravis which was ameliorated by immunosuppressive therapy in combination with chemotherapy. However, the patient subsequently developed pure red cell aplasia and marked lymphocytosis after additional chemotherapy aimed at improvement of thymoma. While a separate immunosuppressive regimen was effective for anemia, lymphocytosis was exacerbated. The biopsied thymoma specimen contained CD4+, CD8+, and CD4+/CD8+ T cells, some of which were CD3-, suggesting immature thymocytes. In contrast, majority of the peripheral lymphocytes were polyclonal CD3+/CD8+/T cell receptor (TCR)αß+ T cells. The CD4/CD8 ratio in the present patient might be affected by immunosuppressive agents, resulting in CD8+ T cell expansion associated with pure red cell aplasia. Although several cases of thymoma accompanied by peripheral T cell lymphocytosis were reported, marked CD8+ T cell proliferation is extremely rare.

Bladder urothelial carcinoma producing insulin-like growth factor II: A case report.

INTRODUCTION: Non-islet cell tumor hypoglycemia is a rare paraneoplastic syndrome associated with tumors. Although it mainly occurs in solid tumors of mesenchymal and epithelial origin, but rarely also in hematopoietic and neuroendocrine origin. CASE PRESENTATION: We describe a 65-year-old man with a muscle-invasive bladder urothelial carcinoma, which rapidly progressed against systemic chemotherapy consisting of gemcitabine and cisplatin. Notably, the patient developed hypoglycemia at the terminal stage of the disease. Pathological diagnosis was giant cell urothelial carcinoma, which was strongly positive for insulin-like growth factor-II in immunohistochemistry. We established patient-derived xenograft from insulin-like growth factor-II producing bladder urothelial carcinoma that caused non-islet cell tumor hypoglycemia. Although we evaluated the efficacy of the neutralizing antibody, there was no statistically significant inhibitory effect on tumor growth. CONCLUSION: To the best of our knowledge, this is the first report of insulin-like growth factor-II-producing urothelial carcinoma that have been recapitulated in a patient-derived xenograft model.

[Simultaneous Hepatorenal Transplantation from a Brain-Dead Donor for Graft Dysfunction and Renal Insufficiency in a Liver Transplant Recipient : A Case Report].

We report a case of lethal hepatorenal insufficiency in a 52-year-old man who received successful simultaneous hepatorenal transplantation from a deceased donor. The patient had undergone live-donor liver transplantation for type-C hepatitis and liver cirrhosis 11 years before he developed graft liver dysfunction due to recurrent viral hepatitis and cirrhosis. At that instance, he also developed end-stage renal dysfunction due to calcineurin inhibitor nephropathy and hepatorenal syndrome. Although he needed three open hemostases and abundant blood transfusion, he was withdrawn from continuous hemodiafiltration on the 55th day and discharged from the hospital on the 272nd day postoperatively. Simultaneous hepatorenal transplantation was reported to be associated with more favorable outcomes of graft function, lower rejection rates, but higher perioperative complication rates compared with liver transplantation alone in patients on hemodialysis. Particularly, close attention should be paid for hemostasis since patients have a hemorrhagic tendency until the recovery of graft liver function.

Retroperitoneal liposarcoma excreting insulin-like growth factor 2 that induced severe hypoglycemia.

Insulin-like growth factor 2 is overexpressed in various cancers, and is associated with a poor prognosis. Also, it is known that insulin-like growth factor 2 is an etiology of non-islet cell tumor hypoglycemia. In this report, we describe a case of unexpected hypoglycemia caused by a dedifferentiated liposarcoma producing insulin-like growth factor 2. A large mass in the retroperitoneum was detected in a 61-year-old man who complained of appetite loss. Despite having no history of diabetes mellitus, hypoglycemia suddenly occurred after admission, but oral glucose therapy was ineffective. After total parenteral nutrition, tumor resection was attempted, but failed as a result of rigid adhesion to the surrounding organs. The patient died of the disease 21 days after surgery. Pathological diagnosis at autopsy revealed dedifferentiated liposarcoma, and immunohistochemical staining showed that the tumor excreted insulin-like growth factor 2. The possibility of an insulin-like growth factor 2-producing tumor should be taken into consideration when we encounter a patient with spontaneous hypoglycemia resistant to glucose substitution therapy.